NOTCH3 variants of unknown significance underpin vascular dysfunction in neurodegenerative disease: a case series of three nfvPPA-FTD patients.

Introduction: The NOTCH3 gene encodes for an evolutionarily conserved protein, whose functions encompass both embryonic cell proliferation and adult tissue-specific differentiation. Among others, a pivotal role in maintaining functional integrity of neurovascular unit (NVU) is supported by the association of several NOTCH3 gene mutations with neuroimaging markers of cerebral small vessel disease (SVD). Indeed, a pathogenic role of NOTCH3 is recognised in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Age of onset moderates the effects of Vascular Risk Factors on Neurodegeneration, Blood-Brain-Barrier permeability, and cognitive decline in Alzheimer's Disease.

Background: The role of Vascular risk factors (VRFs) in the progression of Alzheimer's Disease (AD) and cognitive decline remains to be elucidated, with previous studies resulting in conflicting findings. The possible impact of age-specific mechanisms of resilience/vulnerability is an under addressed issue. We evaluated the association of VRFs with markers of amyloid deposition, neurodegeneration, and blood-brain-barrier (BBB) permeability (Albumin quotient, Qalb), stratifying patients into early-onset (< 65, EOAD), classic late-onset (65-75, cLOAD) and very late-onset (> 75, vLOAD), to evaluate the moderating effect of age of onset.

Lecanemab's Path Forward: Navigating the Future of Alzheimer's Treatment in Europe Amidst the EMA's Rejection.

Lecanemab (Leqembi, Biogen), a humanized anti-amyloid-beta monoclonal antibody, has been approved for early-stage Alzheimer's disease (AD) in several countries, including the US and Japan. However, the European Medicines Agency (EMA) recently issued a negative opinion on its marketing authorization, reflecting concerns over the clinical value and manageability of anti-amyloid treatments. This decision highlights the ongoing disconnect between research advancements and clinical practice, where the focus on biological markers over tangible clinical improvements remains contentious.

Astrocytic-derived vascular remodeling factors are independently associated with blood brain barrier permeability in Alzheimer's disease.

Astrocytes in Alzheimer's disease (AD) exert a pivotal role in the maintenance of blood-brain barrier (BBB) integrity essentially through structural support and release of soluble factors. This study provides new insights into the vascular remodeling processes occurring in AD, and reveals, in vivo, a pathological profile of astrocytic secretion involving Vascular Endothelial Growth Factor (VEGF), Matrix Metalloproteinases (MMP)-9, MMP-2 and Endothelin-1 (ET-1). Cerebrospinal fluid (CSF) levels of VEGF, MMP-2/-9 were lower in patients belonging to the AD continuum, compared to aged-matched controls.

Automatic Voice Disorder Detection from a Practical Perspective.

Voice disorders, such as dysphonia, are common among the general population. These pathologies often remain untreated until they reach a high level of severity. Assisting the detection of voice disorders could facilitate early diagnosis and subsequent treatment.

Constitutive NOS Production Is Modulated by Alzheimer's Disease Pathology Depending on APOE Genotype.

Both the endothelial (eNOS) and the neuronal (nNOS) isoforms of constitutive Nitric Oxide Synthase have been implicated in vascular dysfunctions in Alzheimer's disease (AD). We aimed to explore the relationship between amyloid pathology and NO dynamics by comparing the cerebrospinal fluid (CSF) levels of nNOS and eNOS of 8 healthy controls (HC) and 27 patients with a clinical diagnosis of Alzheimer's disease and isolated CSF amyloid changes, stratified according to APOE ε genotype (APOE ε3 = 13, APOE ε4 = 14). Moreover, we explored the associations between NOS isoforms, CSF AD biomarkers, age, sex, cognitive decline, and blood-brain barrier permeability.

Blood-brain barrier permeability is associated with different neuroinflammatory profiles in Alzheimer's disease.

Introduction: Inflammation is an important player in Alzheimer's disease (AD), whose effects can be influenced by the blood-brain barrier (BBB). Here, we investigated the relationship between BBB permeability, indicated by cerebrospinal fluid (CSF)/plasma albumin quotient (Qalb), and CSF indexes of neuroinflammation in a cohort of biologically defined AD patients.

Methods: Fifty-nine consecutive patients with mild cognitive impairment (MCI) or early AD (Mini-Mental State Examination [MMSE] >22) underwent CSF analysis for inflammatory cytokines (interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, Il-10, IL-12, IL-13, IL-17, tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], granulocyte-monocyte colony-stimulating factor [GM-CSF], granulocyte colony-stimulating factor [G-CSF]).

Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer's disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study.

Background: Despite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ) to detect amyloid pathology, the Aβ/Aβ ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer's disease (AD). However, whether Aβ and amyR have different meanings and whether Aβ represents more than an Aβ-corrective factor remain to be clarified. Our study aimed to compare the ability of Aβ and amyR to detect AD pathology in terms of p-tau/Aβ ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET).

Functional Correlates of Microglial and Astrocytic Activity in Symptomatic Sporadic Alzheimer's Disease: A CSF/F-FDG-PET Study.

Glial and microglial cells contribute to brain glucose consumption and could actively participate in shaping patterns of brain hypometabolism. Here, we aimed to investigate the association between F-fluorodeoxyglucose (F-FDG) uptake and markers of microglial and astrocytic activity in a cohort of patients with Alzheimer's Disease (AD). We dosed cerebrospinal fluid (CSF) levels of soluble Triggering Receptor Expressed on Myeloid cells (sTREM2), Glial Fibrillary Acidic Protein (GFAP), a marker of reactive astrogliosis, and β-S100, a calcium-binding protein associated with a neurotoxic astrocytic profile.

Cerebrospinal Fluid sTREM-2, GFAP, and β-S100 in Symptomatic Sporadic Alzheimer's Disease: Microglial, Astrocytic, and APOE Contributions Along the Alzheimer's Disease Continuum.

Background: Many transversal mechanisms act synergistically at different time-points in the cascade of Alzheimer's disease (AD), since amyloid-β (Aβ) deposition, tau pathology, and neuroinflammation influence each other.

Objective: We explored the contributions of microglia and astrocytes in patients with symptomatic sporadic AD stratified according to AT(N) system and APOE genotype.

Methods: We compared the cerebrospinal fluid (CSF) levels of sTREM-2 and markers of astrocytic activation (GFAP; β-S100) from 71 patients with AD (23 A+T-,48 A+T+; 38 APOEɛ3, 33 APOEɛ4) and 30 healthy controls (HC).

Interplay between the catecholaminergic enzymatic axis and neurodegeneration/neuroinflammation processes in the Alzheimer's disease continuum.

Background And Purpose: The locus coeruleus (LC) provides dopamine/noradrenaline (DA/NA) innervation throughout the brain and undergoes early degeneration in Alzheimer's disease (AD). We evaluated catecholaminergic enzyme levels in the cerebrospinal fluid (CSF) of a group of patients biologically defined as within the AD continuum (ADc) and explored their relationship with AD biomarkers and cytokine/growth factor levels to investigate their interplay with neurodegenerative and neuroinflammatory processes.

Methods: The CSF concentration of DA transporter (DAT), tyrosine-hydroxylase (TH), DOPA-decarboxylase (DDC), and dopamine-β-hydroxylase (DβH), as well as cytokine/growth factor levels, were analyzed in 41 ADc patients stratified according to CSF beta-amyloid (Aβ) (A) and p-tau (T) in AD pathological changes (A+ T-) and AD (A+ T+) subgroups, as well as in 15 control subjects (A- T-).

Functional Correlates of Striatal Dopamine Transporter Cerebrospinal Fluid Levels in Alzheimer's Disease: A Preliminary F-FDG PET/CT Study.

The aim of our study was to investigate regional glucose metabolism with 18F-FDG positron emission tomography/computed tomography in a population of patients with Alzheimer's disease (AD) in relation to cerebrospinal (CSF) levels of striatal dopamine transporter (DAT). All patients underwent lumbar puncture and received a biomarker-based diagnosis of AD. Differences in regional brain glucose metabolism were assessed by Statistical Parametric Mapping version 12 with the use of age, gender, and MMSE as covariates in the analysis.

Periodic sharp wave complexes identify a distinctive phenotype in Creutzfeldt-Jacob disease.

Objective: The aim of our study was to evaluate the diagnostic and prognostic value of Electroencephalogram (EEG), brain Magnetic Resonance Imaging (MRI) and cerebrospinal fluid features, currently representing Creutzfeldt-Jacob Disease (CJD) diagnostic criteria.

Methods: A retrospective study on rapidly progressive dementia patients admitted at the Neurology Clinic of the University of Rome "Tor Vergata" between 2015 and 2020 was conducted. We evaluated clinical, EEG, cerebrospinal fluid and neuroradiological findings.

Neuroimaging findings in leukoencephalopathy with calcifications and cysts: case report and review of the literature.

Leukoencephalopathy with cerebral calcifications and cysts (LCC) is a neurological disorder characterized by the radiological triad of white matter abnormalities, intracranial calcifications and cystic lesions variable in size resulting from a diffuse cerebral microangiopathy. Typically, progressive focal neurological deficits and seizures are the first clinical manifestation, but the severity of symptoms can vary according to the size and location of the cystic lesions holding compressive effects on the surrounding brain tissue. The most common histopathological finding is diffuse microangiopathy, which might be associated to pathogenic mutations in SNORD118 gene causing Labrune syndrome.

Diabetes mellitus contributes to higher cerebrospinal fluid tau levels selectively in Alzheimer's disease patients with the APOE4 genotype.

Background And Purpose: Diabetes mellitus (DM) is considered a risk factor for Alzheimer's disease (AD) and shares some pathological pathways, such as activation of amyloid cascade and tau phosphorylation. The aim of the present study was to investigate to what extent DM could impact on neurodegeneration within the AD continuum, using β amyloid (A: Aβ ) and phosphorylated tau (T: p-tau) biomarkers to discriminate patients by Alzheimer's pathological change (A+/T-) and AD (A+/T+), according to the National Institute on Aging and Alzheimer's Association classification. In addition, we aimed to evaluate whether APOE genotype interacts with tau protein and glucose metabolism dysfunction to affect the pathological process.

Brain energy metabolism and neurodegeneration: hints from CSF lactate levels in dementias.

Mitochondrial dysfunction is pivotal in the development of neurodegenerative dementias, causing cellular death alongside disease-specific pathogenic cascades. Holding cerebrospinal fluid (CSF) lactates as an indirect measure of brain metabolic activity, we first compared CSF lactate levels from patients with Alzheimer's disease (AD)-stratified according to the ATN system and epsilon genotype-frontotemporal dementia (FTD) and dementia with Lewy body (DLB) to findings from healthy controls. With respect to controls, we detected lower CSF lactates in patients with AD and FTD but comparable levels in patients with DLB.

Haemodynamic impairment along the Alzheimer's disease continuum.

Background And Purpose: Alzheimer's disease (AD) is considered a clinical and biological continuum identified via cerebrospinal fluid (CSF) or imaging biomarkers. Chronic hypoperfusion is held as one of the main features of Alzheimer's disease, as part of the processes causing neuronal degeneration. The mechanism responsible for such condition is still debated, although recently a direct connection with amyloid peptides has been shown.

Cognitive reserve and Alzheimer's biological continuum: clues for prediction and prevention of dementia.

Cognitive reserve is originally an epidemiological concept that encompasses individual abilities to cope with changes. It is considered the result of a balance between processes of cellular damage and repair, and its description raised much interest in predicting and preventing cognitive decline in aging and Alzheimer's disease (AD). In this study, we discussed the concept of cognitive reserve considering the recent definition of AD as a biological continuum and suggest that the protection of cognitive reserve may result from efficient synaptic plasticity mechanisms.

Beyond the motor account of amyotrophic lateral sclerosis: Verbal humour and its relationship with the cognitive and pragmatic profile.

Background: Amyotrophic Lateral Sclerosis (ALS) was traditionally described as a disease restricted to the motor system. However, recent findings suggested that it also affects cognition, especially executive functions, social cognition, language and pragmatics. A relevant issue in current research is thus the description of the cognitive phenotype of ALS and the identification of the most vulnerable aspects.

Towards a characterisation of the wild legume bitter vetch (Lathyrus linifolius L. (Reichard) Bässler): heteromorphic seed germination, root nodule structure and N-fixing rhizobial symbionts.

Lathyrus linifolius L. (Reichard) Bässler (Fabiaceae, bitter vetch) is a nitrogen (N) fixing species. A coloniser of low nutrient (N) soils, it supports biodiversity such as key moth and butterfly species, and its roots are known for their organoleptic and claimed therapeutic properties.

Native Seed Supply and the Restoration Species Pool.

Globally, annual expenditure on ecological restoration of degraded areas for habitat improvement and biodiversity conservation is approximately $18bn. Seed farming of native plant species is crucial to meet restoration goals, but may be stymied by the disconnection of academic research in seed science and the lack of effective policies that regulate native seed production/supply. To illustrate this problem, we identified 1,122 plant species important for European grasslands of conservation concern and found that only 32% have both fundamental seed germination data available and can be purchased as seed.

Traditional knowledge on wild and cultivated plants in the Kilombero Valley (Morogoro Region, Tanzania).

Background: This research was performed in four villages adjacent the boundary of Udzungwa Mountains National Park in the Kilombero River plain of Tanzania. The area adjacent the villages is characterized by self-consumption agriculture, with a population that is on average poor, still very tied to traditions and almost entirely unaffected by modernization and technology. The aim of the present study was to investigate and record local knowledge regarding the use of wild and traditionally cultivated plants used for traditional medicine and for other everyday purposes (e.

Climate warming could increase recruitment success in glacier foreland plants.

Background And Aims: Glacier foreland plants are highly threatened by global warming. Regeneration from seeds on deglaciated terrain will be crucial for successful migration and survival of these species, and hence a better understanding of the impacts of climate change on seedling recruitment is urgently needed to predict future plant persistence in these environments. This study presents the first field evidence of the impact of climate change on recruitment success of glacier foreland plants.